The Extracellular Matrix of the Renal Medulla as a Dynamic Reservoir of Osmolytes

Abstract

The ability of mammalian kidneys to concentrate urine to 1200-1400 mOsm/kg is traditionally explained by the classical countercurrent multiplication theory; however, this model leaves at least three fundamental questions unanswered. First, the medullary osmotic gradient maintains remarkable stability even under high blood flow in the vasa recta, which theoretically should lead to massive washout of osmolytes; mathematical models demonstrate that countercurrent exchange alone cannot explain this resilience. Second, experimental studies from the 1960s-1980s revealed pleiotropic effects of antidiuretic hormone that extend far beyond simple regulation of aquaporin-2 at the epithelial level. Third, phenotypic variability in patients with similar V2 receptor or AQP2 mutations suggests the existence of additional modulating mechanisms whose nature remains enigmatic.

In this review, we integrate classical theory with contemporary data on the role of the medullary interstitial matrix, particularly hyaluronic acid, as a dynamic reservoir of osmolytes. Literature analysis confirms that HA concentration in the medulla is 3-5 times higher than in the cortex, and that this polyanionic macromolecule can immobilize Na⁺ and urea through electrostatic interactions. Particularly compelling are the classical experiments of Rowen and Law (1981), which demonstrated that immunoneutralization of renal hyaluronidase with specific antiserum suppresses the concentrating response to ADH by 60-70%, leaving approximately one-third of the effect intact. This observation elegantly aligns with a dual-action model of ADH: the epithelial mechanism via V2R→cAMP→PKA→AQP2 provides rapid increase in water permeability, while the matrix mechanism via cAMP→hyaluronidase→HA depolymerization releases immobilized osmolytes, increasing the effective interstitial osmolarity. This multilevel integration not only explains the stability of the osmotic gradient under variable hemodynamic conditions but also opens new horizons for understanding the pathophysiology of urine concentrating defects and developing personalized therapeutic strategies.